Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor.
We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human alpha7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl- currents. The concomitant increase in apparent affinity and cooperativity of the dose-response curve suggest that ivermectin acts as a positive allosteric effector. This interpretation is supported by the observation of an increase in efficiency of a partial agonist associated with the potentiation and by the differential effect of ivermectin on mutants within the M2 channel domain. Ivermectin effects reveal a novel allosteric site for pharmacological agents on neuronal alpha7 nicotinic acetylcholine receptors.
Krause
R M
RM
Department of Physiology, University Medical Center, 1211 Geneva 4, Switzerland.
Buisson
B
B
Bertrand
S
S
Corringer
P J
PJ
Galzi
J L
JL
Changeux
J P
JP
Bertrand
D
D
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D002645:Chickens; D018118:Chloride Channels / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating; D007559:Ivermectin / Q000494:pharmacology*; D008564:Membrane Potentials; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009865:Oocytes; D017354:Point Mutation; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects*; D011994:Recombinant Proteins; D012995:Solubility; D013329:Structure-Activity Relationship; D014162:Transfection; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000871:Anthelmintics; D018118:Chloride Channels; C579167:Chrna7 protein, human; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007559:Ivermectin